Publications by authors named "Douglas Jacoby"

26 Publications

  • Page 1 of 1

Implementation of a Machine-Learning Algorithm in the Electronic Health Record for Targeted Screening for Familial Hypercholesterolemia: A Quality Improvement Study.

Circ Cardiovasc Qual Outcomes 2021 Jun 10:CIRCOUTCOMES120007641. Epub 2021 Jun 10.

Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. (S.S., P.L., A.B., M.C., J.H., D.S., G.W., M.R., D.R., D.J.).

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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.007641DOI Listing
June 2021

Incremental prognostic value of visually estimated coronary artery calcium in patients undergoing positron emission tomography imaging.

Open Heart 2021 May;8(1)

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Objective: Visually estimated coronary artery calcium (VECAC) from chest CT or attenuation correction (AC)/CT obtained during positron emission tomography (PET)-myocardial perfusion imaging (MPI) is feasible. Our aim was to determine the prognostic value of VECAC beyond conventional risk factors and PET imaging parameters, including coronary flow reserve (CFR).

Methods: We analysed 608 patients without known coronary artery disease who underwent PET-MPI between 2012 and 2016 and had AC/CT and/or chest CT images. We used Cox regression to estimate the association of VECAC categories (≤10, 11-400, >400 Agatston units (AU)) with the primary outcome of all-cause death, acute coronary syndrome or stroke (mean follow-up 4.3±1.8 years). C-statistics assessed the relationship between PET parameters and VECAC with the primary outcome.

Results: Mean age was 58±11 years, 65% were women and 67% were black. VECAC ≤10, 11-400 and >400 AU was observed in 68%, 12% and 20% of subjects, respectively. Compared with VECAC ≤10, VECAC categories 11-400 (HR 2.25, 95% CI 1.24 to 4.08) and >400 AU (HR 3.05, 95% CI 1.87 to 4.98) were associated with the primary outcome after adjusting for traditional risk factors, MPI findings and CFR. Adding VECAC to a model that included PET-MPI, CFR and clinical risk factors improved the prognostic value for the primary outcomes (c-statistic 0.71 to 0.75 with VECAC, p=0.01).

Conclusions: VECAC is a potent predictor of events beyond traditional risk factors and PET imaging markers, including CFR. These data further support the importance for routine VECAC implementation.
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http://dx.doi.org/10.1136/openhrt-2021-001648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108688PMC
May 2021

The Use of Subclinical Atherosclerosis Imaging to Guide Preventive Cardiology Management.

Curr Cardiol Rep 2021 05 7;23(6):61. Epub 2021 May 7.

Division of Cardiovascular Medicine, University of Pennsylvania Health System, Pennsylvania Hospital, Philadelphia, PA, USA.

Purpose Of The Review: Clinical atherosclerotic cardiovascular disease (ASCVD) requires years to manifest, providing a window of opportunity for preventive cardiovascular management. Subclinical atherosclerosis imaging leverages this long latency period to estimate and improve future ASCVD risk.

Recent Findings: Coronary artery calcium (CAC) scoring has the most robust data in the detection of subclinical atherosclerosis. CAC scan significantly enhances cardiovascular risk stratification in addition to traditional risk models. Coronary computed tomography angiography data show similar strengths in subclinical atherosclerosis detection in addition to plaque morphology characterization with inherent limitations. Carotid intima-media thickness and ankle-brachial index are other modalities whose predictive value becomes incremental when added to the aforementioned modalities. When added to traditional risk models, subclinical atherosclerosis imaging modalities personalize future ASCVD risk stratification and assist in the initiation and rate of intensification of preventive therapies. Emerging imaging techniques exist but further research is required for primetime clinical use.
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http://dx.doi.org/10.1007/s11886-021-01490-7DOI Listing
May 2021

Effect of Passive Choice and Active Choice Interventions in the Electronic Health Record to Cardiologists on Statin Prescribing: A Cluster Randomized Clinical Trial.

JAMA Cardiol 2021 Jan;6(1):40-48

Penn Medicine, University of Pennsylvania, Philadelphia.

Importance: Statin therapy is underused for many patients who could benefit.

Objective: To evaluate the effect of passive choice and active choice interventions in the electronic health record (EHR) to promote guideline-directed statin therapy.

Design, Setting, And Participants: Three-arm randomized clinical trial with a 6-month preintervention period and 6-month intervention. Randomization conducted at the cardiologist level at 16 cardiology practices in Pennsylvania and New Jersey. The study included 82 cardiologists and 11 693 patients. Data were analyzed between May 8, 2019, and January 9, 2020.

Interventions: In passive choice, cardiologists had to manually access an alert embedded in the EHR to select options to initiate or increase statin therapy. In active choice, an interruptive EHR alert prompted the cardiologist to accept or decline guideline-directed statin therapy. Cardiologists in the control group were informed of the trial but received no other interventions.

Main Outcomes And Measures: Primary outcome was statin therapy at optimal dose based on clinical guidelines. Secondary outcome was statin therapy at any dose.

Results: The sample comprised 11 693 patients with a mean (SD) age of 63.8 (9.1) years; 58% were male (n = 6749 of 11 693), 66% were White (n = 7683 of 11 693), and 24% were Black (n = 2824 of 11 693). The mean (SD) 10-year atherosclerotic cardiovascular disease (ASCVD) risk score was 15.4 (10.0); 68% had an ASVCD clinical diagnosis. Baseline statin prescribing rates at the optimal dose were 40.3% in the control arm, 39.1% in the passive choice arm, and 41.2% in the active choice arm. In adjusted analyses, the change in statin prescribing rates at optimal dose over time was not significantly different from control for passive choice (adjusted difference in percentage points, 0.2; 95% CI, -2.9 to 2.8; P = .86) or active choice (adjusted difference in percentage points, 2.4; 95% CI, -0.6 to 5.0; P = .08). In adjusted analyses of the subset of patients with clinical ASCVD, the active choice intervention resulted in a significant increase in statin prescribing at optimal dose relative to control (adjusted difference in percentage points, 3.8; 95% CI, 1.0-6.4; P = .008). No other subset analyses were significant. There were no significant changes in statin prescribing at any dose for either intervention.

Conclusions And Relevance: The passive choice and active choice interventions did not change statin prescribing. In the subgroup of patients with clinical ASCVD, the active choice intervention led to a small increase in statin prescribing at the optimal dose, which could inform the design or targeting of future interventions.

Trial Registration: ClinicalTrials.gov Identifier: NCT03271931.
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http://dx.doi.org/10.1001/jamacardio.2020.4730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542520PMC
January 2021

Progression of retinopathy and incidence of cardiovascular disease: findings from the Chronic Renal Insufficiency Cohort Study.

Br J Ophthalmol 2021 02 5;105(2):246-252. Epub 2020 Jun 5.

Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Purpose: Chronic kidney disease (CKD) patients often develop cardiovascular disease (CVD) and retinopathy. The purpose of this study was to assess the association between progression of retinopathy and concurrent incidence of CVD events in participants with CKD.

Design: We assessed 1051 out of 1936 participants in the Chronic Renal Insufficiency Cohort Study that were invited to have fundus photographs obtained at two timepoints separated by 3.5 years, on average.

Methods: Using standard protocols, presence and severity of retinopathy (diabetic, hypertensive or other) and vessel diameter calibre were assessed at a retinal image reading centre by trained graders masked to study participants' information. Participants with a self-reported history of CVD were excluded. Incident CVD events were physician adjudicated using medical records and standardised criteria. Kidney function and proteinuria measurements along with CVD risk factors were obtained at study visits.

Results: Worsening of retinopathy by two or more steps in the EDTRS retinopathy grading scale was observed in 9.8% of participants, and was associated with increased risk of incidence of any CVD in analysis adjusting for other CVD and CKD risk factors (OR 2.56, 95% CI 1.25 to 5.22, p<0.01). After imputation of missing data, these values were OR=1.66 (0.87 to 3.16), p=0.12.

Conclusion: Progression of retinopathy is associated with higher incidence of CVD events, and retinal-vascular pathology may be indicative of macrovascular disease even after adjustment for kidney diseases and CVD risk factors. Assessment of retinal morphology may provide important information when assessing CVD in patients with CKD.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315333DOI Listing
February 2021

The "Centrality of Sepsis": A Review on Incidence, Mortality, and Cost of Care.

Healthcare (Basel) 2018 Jul 30;6(3). Epub 2018 Jul 30.

Department of Cardiology, Penn Presbyterian Medical Center, 51 N 39th St, Philadelphia, PA 19104, USA.

Sepsis is a serious and fatal medical condition that has overburdened the US healthcare system. The purpose of this paper is to provide a review of published literature on severe sepsis with a distinct focus on incidence, mortality, cost of hospital care, and postdischarge care. A review of the nature of postsepsis syndrome and its impact on septic patients is also included. The literature review was conducted utilizing the PubMed database, identifying 34 studies for inclusion. From the evaluation of these studies, it was determined that the incidence of sepsis continues to be on the rise according to three decades of epidemiological data. Readmissions, mortality, and length of stay were all higher among septic patients when compared to patients treated for other conditions. The cost of treating sepsis is remarkably high and exceeds the cost of treating patients with congestive heart failure and acute myocardial infarction. The overall cost of sepsis is reflective of not only the cost of initial hospitalization but also the postdischarge care costs, including postsepsis syndrome and cognitive and functional disabilities that require a significant amount of healthcare resources long term. Sepsis and its impact on patients and the US healthcare system is a current quality-of-life and cost-burden issue that needs to be addressed with a greater focus on preventative strategies.
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http://dx.doi.org/10.3390/healthcare6030090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164723PMC
July 2018

A Clinical Guide to Combination Lipid-Lowering Therapy.

Curr Atheroscler Rep 2018 03 7;20(4):19. Epub 2018 Mar 7.

Cardiovascular Division, Department of Medicine, University of Pennsylvania Health System, Philadelphia, PA, USA.

Purpose Of Review: We provide an overview of our current understanding of combination lipid-lowering therapies intended for dyslipidemia treatment and cardiovascular disease prevention. First, we analyze recent statin and non-statin combination therapy guidelines and clinical studies since the publication of 2013 American College of Cardiology Cholesterol Guidelines. Second, we examine the clinical utility of non-statin agents alone and in combination in terms of LDL-C lowering and ASCVD risk reduction.

Recent Findings: Medical societies, including the American College of Cardiology (ACC), National Lipid Association (NLA), and American Association of Clinical Endocrinologists (AACE), have released guidelines to address the appropriate use of non-statin therapies. The guidelines incorporated new evidence, including the IMPROVE-IT and FOURIER clinical trials, which demonstrate that the combination of statin therapy with other non-statin agents such as ezetimibe and PCSK9 inhibitors has a significant clinical benefit. Increasing evidence that aggressive low-density lipoprotein cholesterol (LDL-C) lowering leads to lower cardiovascular disease risk supports the need for continued exploration of the role of combination lipid-lowering therapies. A review of guidelines and clinical trials evaluating non-statin agents illuminates the growing base of evidence and expert opinion supporting the use of combination lipid-lowering therapies. While the majority of clinical trial data utilizes dyslipidemia monotherapy, especially statins, combination therapies represent an opportunity for individualized, patient-centered approach to LDL-C lowering and atherosclerotic cardiovascular disease (ASCVD) risk reduction. The overview provides a perspective on lipid management intended for clinicians who seek additional information and guidance on the use of combination therapies.
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http://dx.doi.org/10.1007/s11883-018-0721-2DOI Listing
March 2018

Improving cardiovascular outcomes by intensifying low density lipoprotein lowering therapy in high-risk patients.

Eur Heart J 2016 12 14;37(48):3585-3587. Epub 2016 Oct 14.

Perelman School of Medicine of the University of Pennsylvania, USA

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http://dx.doi.org/10.1093/eurheartj/ehw447DOI Listing
December 2016

Updated cholesterol guidelines and intensity of statin therapy.

J Clin Lipidol 2015 May-Jun;9(3):357-9. Epub 2014 Dec 24.

Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Background: In November 2013, the American College of Cardiology and the American Heart Association released new cholesterol guidelines. Implications of these new guidelines for statin prescription remain uncertain, particularly in individuals already on statin therapy.

Objective: Our objective was to examine the impact of the guidelines on the intensity of statin therapy at a large academic medical center.

Methods: We queried the electronic health record at the University of Pennsylvania Health System to evaluate current practice patterns at a large academic institution in patients already on statin therapy.

Results: Among 40,036 statin-treated patients, 47% of patients may warrant an intensification of statin therapy according to the updated national cholesterol guidelines.

Conclusions: These findings highlight the magnitude of potential changes in statin prescription patterns favoring higher potency statin therapy, a sizable shift that parallels the predicted increase in statin initiation.
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http://dx.doi.org/10.1016/j.jacl.2014.12.009DOI Listing
March 2016

Carotid intima-media thickness measurement promises to improve cardiovascular risk evaluation in head and neck cancer patients.

Clin Cardiol 2015 May 11;38(5):280-4. Epub 2015 May 11.

Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.

Background: Radiation-treated head and neck cancer (HNC) patients are at high risk for developing radiation vasculopathy, as evidenced by an increased stroke risk. The benefits of screening and assessing the cardiovascular (CV) risk of HNC patients using carotid intima-media thickness (CIMT) ultrasound are not known. Our objective was to determine the prevalence of high CV risk in patients without known CV diseases who received radiation for HNC, determine the percentage of screened patients who had a change in clinical management as a result of an increased CIMT, and to compare this risk-assessment tool to patients' risk classification using the Framingham Risk Score (FRS) and Pooled Cohort Atherosclerotic Cardiovascular Disease (ASCVD) Risk Equation (recommended by American College of Cardiology/American Heart Association Guidelines on the Assessment of Cardiovascular Risk).

Hypothesis: Risk calculators may not accurately predict risk in this population with a unique risk factor. Carotid IMT may be used to detect radiation vasculopathy in HNC patients.

Methods: Retrospective medical chart review was conducted on 134 radiation-treated HNC patients. The main outcome measures were CV risk (as determined by CIMT) and clinical management. Also, the FRS and the Pooled Cohort ASCVD Risk Equation were used to compare classification with CIMT.

Results: Approximately 74% of the cases were at high CV risk using CIMT technique. Approximately half of the HNC patients screened had a change in clinical management characterized by recorded initiation of aspirin and recorded initiation or increase of statin therapies. The FRS and the Pooled Cohort ASCVD Risk Equation failed to detect 40% to 50% of cases found to be at high risk using the CIMT technique.

Conclusions: Carotid IMT identified a much greater percentage of radiation-treated HNC patients at high CV risk compared with standard CV-risk calculators. By more accurately identifying the patients at high risk, this may lead to more effective prevention, and therefore a reduction in CV events.
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http://dx.doi.org/10.1002/clc.22389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711104PMC
May 2015

Advanced lipid testing: when, why, and in whom?

Rev Cardiovasc Med 2014 ;15(4):310-7; quiz 318-9

Baylor University Medical Center at Dallas, Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX; The Heart Hospital, Plano, TX.

Atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality in developed countries. The management of blood cholesterol with the use of statin drugs in at-risk patients is a pillar of medical therapy for the primary and secondary prevention of cardiovascular disease. Although the standard lipid panel is adequate to accurately assess cardiovascular disease risk in most patients, there are some situations in which conventional cholesterol testing does not fully identify cardiovascular risk or reflect disease progression. A number of advanced lipid tests can assist the clinician when assessing a patient's cardiovascular disease risk, including measurement of low-density lipoprotein particle number.
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April 2015

Differences in absolute risk of cardiovascular events using risk-refinement tests: a systematic analysis of four cardiovascular risk equations.

Atherosclerosis 2013 Mar 31;227(1):172-7. Epub 2012 Dec 31.

Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, PA, USA.

Background: Current cardiovascular risk assessment guidelines incorporate judicious use of C-reactive protein (CRP), carotid intima-media thickness (CIMT), and coronary artery calcium (CAC) in selected populations and describe threshold levels for higher and lower cardiovascular risk for each of the three risk refinement tests. However, the effect of these suggested thresholds of relative risk on absolute global risk remains uncertain.

Methods: Systematic permutation of risk factors provided 10-year risk estimates using the Framingham risk score, equations derived from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Atherosclerosis Risk in Communities (ARIC) study, and the Reynolds risk score. Low-, high-, and very-high-risk values of CAC, CIMT, and hsCRP were defined as: 0, 100, 400 Agatston units; 25th percentile without plaque, 75th percentile without plaque, 75th percentile with plaque; and 1.0, 3.0, 7.0 mg/L.

Results: Incorporation of low-, high-, and very-high-risk CAC values using the MESA risk score resulted in greater changes in absolute risk from the Framingham risk score than the addition of either CIMT or hsCRP values using the ARIC or Reynolds risk scores.

Conclusions: Although certain values of CAC, CIMT, and hsCRP have been similarly designated as low, high, or very-high risk, incorporation of these thresholds into validated risk equations yielded substantially different levels of absolute cardiovascular risk. Use of available risk equations may be advisable to calculate absolute risk rather than relying on risk-marker thresholds derived from relative risk estimates.
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http://dx.doi.org/10.1016/j.atherosclerosis.2012.12.025DOI Listing
March 2013

Agents that bind annexin A2 suppress ocular neovascularization.

J Cell Physiol 2010 Nov;225(3):855-64

Department of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.

TM601 is a synthetic polypeptide with sequence derived from the venom of the scorpion Leiurus quinquestriatus that has anti-neoplastic activity. It has recently been demonstrated to bind annexin A2 on cultured tumor and vascular endothelial cells and to suppress blood vessel growth on chick chorioallantoic membrane. In this study, we investigated the effects of TM601 in models of ocular neovascularization (NV). When administered by intraocular injection, intravenous injections, or periocular injections, TM601 significantly suppressed the development of choroidal NV at rupture sites in Bruch's membrane. Treatment of established choroidal NV with TM601 caused apoptosis of endothelial cells and regression of the NV. TM601 suppressed ischemia-induced and vascular endothelial growth factor-induced retinal NV and reduced excess vascular permeability induced by vascular endothelial growth factor. Immunostaining with an antibody directed against TM601 showed that after intraocular or periocular injection, TM601 selectively bound to choroidal or retinal NV and co-localized with annexin A2, which is undetectable in normal retinal and choroidal vessels, but is upregulated in endothelial cells participating in choroidal or retinal NV. Intraocular injection of plasminogen or tissue plasminogen activator, which like TM601 bind to annexin A2, also suppressed retinal NV. This study supports the hypothesis that annexin A2 is an important target for treatment of neovascular diseases and suggests that TM601, through its interaction with annexin A2, causes suppression and regression of ocular NV and reduces vascular leakage and thus may provide a new treatment for blinding diseases such as neovascular age-related macular degeneration and diabetic retinopathy.
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http://dx.doi.org/10.1002/jcp.22296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005718PMC
November 2010

Potent pleiotropic anti-angiogenic effects of TM601, a synthetic chlorotoxin peptide.

Anticancer Res 2010 Jan;30(1):39-46

TransMolecular, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA.

Unlabelled: Chemically synthesized chlorotoxin (TM601) has been studied as a tumor targeting peptide. In this study, the anti-angiogenic properties of TM601 are reported.

Materials And Methods: In vitro and in vivo models of angiogenesis and tumor growth were used to characterize the anti-angiogenic effects of TM601.

Results: TM601 bound to proliferating vascular endothelial cells, decreased human umbilical vein endothelial cell (HUVEC) invasion, and reduced secretion of bioactive matrix metalloproteinase-2 (MMP-2). Using the chick chorioallantoic membrane assay (CAM), TM601 inhibited angiogenesis stimulated by any of eight pro-angiogenic factors, and when TM601 was co-administered with bevacizumab, the combination was significantly more potent than a ten-fold increase in bevacizumab dose. TM601 did not alter tumor or vascular endothelial cell growth in vitro, but TM601 treatment of tumors grown on the CAM decreased tumor growth and intra-tumoral hemoglobin levels. Intravenously injected TM601 was also shown to significantly decrease new blood vessel growth in mice.

Conclusion: TM601 inhibits angiogenesis stimulated by many factors and potentiates the anti-angiogenic effect of bevacizumab.
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January 2010

Annexin A2 is a molecular target for TM601, a peptide with tumor-targeting and anti-angiogenic effects.

J Biol Chem 2010 Feb 15;285(7):4366-74. Epub 2009 Dec 15.

TransMolecular Inc., Cambridge, Massachusetts 02139, USA.

TM601 is a synthetic form of chlorotoxin, a 36-amino acid peptide derived from the venom of the Israeli scorpion, Leirius quinquestriatus, initially found to specifically bind and inhibit the migration of glioma cells in culture. Subsequent studies demonstrated specific in vitro binding to additional tumor cell lines. Recently, we demonstrated that proliferating human vascular endothelial cells are the only normal cell line tested that exhibits specific binding to TM601. Here, we identify annexin A2 as a novel binding partner for TM601 in multiple human tumor cell lines and human umbilical vein endothelial cell (HUVEC). We demonstrate that the surface binding of TM601 to the pancreatic tumor cell line Panc-1 is dependent on the expression of annexin A2. Identification of annexin A2 as a binding partner for TM601 is also consistent with the anti-angiogenic effects of TM601. Annexin A2 functions in angiogenesis by binding to tissue plasminogen activator and regulating plasminogen activation on vascular endothelial cells. We demonstrate that in HUVECs, TM601 inhibits both vascular endothelial growth factor- and basic fibroblast growth factor-induced tissue plasminogen activator activation, which is required for activation of plasminogen to plasmin. Consistent with inhibition of cell surface protease activity, TM601 also inhibits platelet-derived growth factor-C induced trans-well migration of both HUVEC and U373-MG glioma cells.
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http://dx.doi.org/10.1074/jbc.M109.066092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836041PMC
February 2010

Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601).

Expert Opin Drug Deliv 2007 Mar;4(2):175-86

Cedars-Sinai Medical Center, Maxine Dunitz Neurosurgical Institute, Department of Neurosurgery, Los Angeles, CA8631 W. Third Street, Suite 800e, Los Angeles, CA 90048, USA.

Targeted therapies for cancer is a rapidly advancing field, but the identification of tumor-specific ligands has proven difficult. Chlorotoxin (CTX) is a small, 36 amino acid neurotoxin isolated from the venom of the Giant Yellow Israeli scorpion Leiurus Quinquestriatus. Interestingly, the peptide has been found to preferentially bind to a variety of human malignancies, but shows little or no binding to normal human tissues. A synthetic version of this peptide (TM-601) has been manufactured and covalently linked to iodine 131 (131I-TM-601) as a means of targeting radiation to tumor cells. Preclinical studies and Phase I clinical trials have been completed in patients with recurrent glioma, a type of malignant brain tumor. These studies demonstrated that intracavitary dosing of 131I-TM-601 appears safe, minimally toxic, and binds malignant glioma with high affinity and for long durations. A Phase II trial of this agent using higher doses of radioactivity and repeated local administrations is underway. In addition, enrolment has begun in a Phase I trial evaluating whether systemically delivered 131I-TM-601 can be used to image metastatic solid tumors and primary gliomas. Due to its small size, selective tumor binding properties, minimal toxicity and relative ease of manipulation, CTX represents a potentially important targeting agent for many cancers.
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http://dx.doi.org/10.1517/17425247.4.2.175DOI Listing
March 2007

Safety and feasibility of percutaneous autologous skeletal myoblast transplantation in the coil-infarcted swine myocardium.

J Pharmacol Toxicol Methods 2006 Jul-Aug;54(1):71-7. Epub 2006 Feb 3.

Arizona Heart Institute, Phoenix, USA.

Introduction: Autologous skeletal myoblast transplantation (ASMT) for myocardial regeneration is a promising new treatment for patients with congestive heart failure secondary to myocardial infarction (MI). However, non-surgical delivery could broaden the utility of this approach. The present study was designed to evaluate the safety and feasibility of transplanting autologous skeletal myoblast (ASM) via endovascular delivery into the infarcted swine myocardium.

Methods: Seven female Yorkshire swine successfully underwent induced left ventricular MI. ASM biopsies were obtained from the hind limb of each animal and myoblasts were expanded in vitro. In a pilot experiment, ASM were labeled with iridium and short-term retention and biodistribution was determined 2 h after ASM delivery via the MyoStar needle-injection catheter inserted through the femoral artery. At 30 days post-infarction, the remaining animals were divided into three groups containing 2 animals each for percutaneous catheter delivery into the infarcted zone: group 1 control animals were injected with media only, group 2 and 3 animals were injected with approximately 300 x 10(6) and 600 x 10(6) ASM, respectively. Sixty days post-transplantation, the swine hearts were harvested.

Results: During the 60-day period between transplantation and harvest, no adverse events were recorded, and continuous rhythm monitoring revealed no arrhythmias. In the small sampling size, myocardial function assessments revealed a trend toward improvement in the treatment groups with respect to ejection fraction, viability, and cardiac index. However, histology of treated swine hearts identified no skeletal muscle cells.

Discussion: Percutaneous ASMT into an infarcted swine myocardium is feasible and safe, and may contribute to overall improved heart function.
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http://dx.doi.org/10.1016/j.vascn.2005.12.002DOI Listing
October 2006

Correlation of autologous skeletal myoblast survival with changes in left ventricular remodeling in dilated ischemic heart failure.

J Thorac Cardiovasc Surg 2005 Oct 2;130(4):1001. Epub 2005 Sep 2.

Department of Surgery, The Ohio State University, Columbus, Ohio, USA.

Objectives: The effect of autologous skeletal myoblast transplantation has not been rigorously studied in the setting of end-stage ischemic heart failure free of concomitant coronary revascularization. The aims of the present study were to determine autologous skeletal myoblast survival and its effects on left ventricular function and remodeling in sheep with dilated ischemic heart failure.

Methods: Ischemic heart failure (left ventricular ejection fraction, 30% +/- 2%; left ventricular end-systolic volume index, 82 +/- 9 mL/m2) was created in sheep (n = 11) with serial left circumflex coronary artery microembolizations. Instruments were inserted for the long-term determination of left ventricular global and regional dimensions, hemodynamics, and pressure-volume analysis after autologous skeletal myoblast transplantation (approximately 3.0 x 10(8) myoblasts; heart failure plus autologous skeletal myoblast group, n = 5) or without (heart failure-control group, n = 6). Measurements were performed in conscious animals.

Results: Autologous skeletal myoblast-derived skeletal muscle was found in all injected animals at 6 weeks. In ischemic heart failure, autologous skeletal myoblast cardiomyoplasty failed to improve systolic (left ventricular ejection fraction, 29% +/- 4%; dP/dT(max), 2863 +/- 152 mm Hg/s; end-systolic elastance, 1.6 +/- 0.22) or diastolic (left ventricular end-diastolic pressure, 21 +/- 2 mm Hg; time constant of relaxation (Tau), 34 +/- 4 ms; dP/dT(min), -1880 +/- 68 mm Hg/s) function. There was, however, attenuation in the left ventricular dilatation after autologous skeletal myoblast transplantation (change in end-systolic volume index, 14% +/- 4% vs 32% +/- 6%; P < .05). The effects of autologous skeletal myoblast-derived skeletal muscle were exclusive to the left ventricular short-axis dimension and dependent on autologous skeletal myoblast survival (R2 = 0.59, P = .006, n = 11).

Conclusions: Autologous skeletal cardiomyoplasty was able to attenuate left ventricular remodeling in sheep with end-stage ischemic heart failure.
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http://dx.doi.org/10.1016/j.jtcvs.2005.02.030DOI Listing
October 2005

Drug treatment of intermittent claudication.

Drugs 2004 ;64(15):1657-70

Department of Medicine, Cardiovascular Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

The US FDA has approved two drugs for the management of intermittent claudication: pentoxifylline and cilostazol. The mechanism of action that provides symptom relief with pentoxifylline is poorly understood but is thought to involve red blood cell deformability as well as a reduction in fibrinogen concentration, platelet adhesiveness and whole blood viscosity. The recommended dose of pentoxifylline is 400 mg three times daily with meals. Cilostazol is a potent, reversible, phosphodiesterase III inhibitor. The inhibition of phosphodiesterase allows for the increased availability of cyclic adenosine monophosphate (cAMP). cAMP mediates many agonist-induced platelet inhibitory, vasodilatory and vascular antiproliferative responses. Cilostazol, at a dose of 100 mg twice daily, is recommended to be taken 30 minutes before or 2 hours after breakfast and dinner. In addition to pentoxifylline and cilostazol, clinical trials indicate many other drugs may relieve the symptoms of intermittent claudication. Ginkgo biloba, available as an over-the-counter extract, provides symptom relief comparable to pentoxifylline. Two European agents, naftidrofuryl and buflomedil, also have efficacy that is reported to be similar to pentoxifylline. Policosanol is a mixture of fatty alcohols derived from honeybee wax which, according to very limited data, reduces symptoms of claudication. Amino acids, certain peptides and prostaglandins may have a therapeutic role. Finally, novel approaches including angiogenesis mediated by growth factors, are currently under investigation.
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http://dx.doi.org/10.2165/00003495-200464150-00004DOI Listing
November 2004

Preclinical evaluation of a novel intracerebral microinjection instrument permitting electrophysiologically guided delivery of therapeutics.

Neurosurgery 2004 Jun;54(6):1497-507; discussion 1507

Laboratory for Neural Reconstruction, Program in Neuroscience, Harvard Medical School, and Department of Psychiatry, McLean Hospital, Belmont, Massachusetts, USA.

Objective: This series of studies was designed to evaluate the function of a new neurosurgical instrument for precision injection of therapeutics within the central nervous system.

Methods: An intracerebral microinjection instrument was designed to 1) allow multiple injections to be placed in three-dimensional space within a target structure from a single proximal brain penetration, 2) incur minimal injury at the site of injection, 3) enable accurate microvolume injections, and 4) permit electrophysiological recording during the injection procedure. Rats received injections of fluorescent microspheres or suspensions of labeled cells to test instrument function and level of induced trauma. A rodent model of stroke was used to test the instrument's ability to record electrocorticograms or somatosensory evoked potentials from normal and damaged tissue.

Results: Microliter volumes of fluorescent microspheres were accurately placed at predetermined sites within the rat striatum. Reactive gliosis was markedly reduced using the intracerebral microinjection instrument when compared with standard cannulas. In a stroke model, electrophysiological recording with the instrument allowed discrimination between viable and nonviable ischemic tissue, and function of pathways or circuits was assessed using evoked potentials. Embryonic stem cells grafted immediately after electrophysiological recordings demonstrated robust long-term survival.

Conclusion: The intracerebral microinjection instrument enables electrophysiologically guided microinjection of therapeutics to target areas with exquisite accuracy while incurring minimal local trauma and reactive gliosis at the injection site. The instrument also permits minimally invasive, multiple injections to be disseminated in three-dimensional space within the target region from a single proximal penetration of the brain.
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http://dx.doi.org/10.1227/01.neu.0000125007.03145.00DOI Listing
June 2004

Noninvasive atherosclerosis imaging for predicting cardiovascular events and assessing therapeutic interventions.

Curr Atheroscler Rep 2004 Jan;6(1):20-6

Department of Cardiology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.

Noninvasive assessment of atherosclerosis offers an opportunity to provide individual cardiovascular risk management and an opportunity to monitor the efficacy of therapy targeted toward atherosclerosis. The three imaging modalities that currently hold the most promise at the clinical and research levels are ultrasound for carotid intima-media thickness, computed tomography for coronary artery calcification, and magnetic resonance imaging for carotid and aortic plaque imaging. The following review describes the evidence that validates each technique as a surrogate marker of atherosclerosis, with an emphasis on cardiovascular events and the progression of disease. Both the particular strengths and limitations of each imaging modality are discussed.
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http://dx.doi.org/10.1007/s11883-004-0112-8DOI Listing
January 2004

Triple immune suppression increases short-term survival of porcine fetal retinal pigment epithelium xenografts.

Invest Ophthalmol Vis Sci 2003 Sep;44(9):4044-53

Department of Ophthalmology, Harkness Eye Institute, Columbia University, New York, New York 10032, USA.

Purpose: To determine the effect of triple drug immune suppression on RPE xenograft survival in the fetal pig after transplantation into the albino rabbit subretinal space.

Methods: Primary RPE microaggregates (approximately 40,000 RPE cells) were injected into the subretinal space of 24 albino rabbits, with half the rabbits maintained on triple systemic immune suppression. RPE survival was estimated with a DNA probe (porcine DNA repeat element; PRE) against a porcine-specific repetitive chromosomal marker or a RAM-11 antibody against rabbit macrophages.

Results: Numerous pigmented cells were visible in the subretinal space at all time points, but most pigment-containing cells 4 weeks or more after surgery were RAM-11 positive and PRE negative. The number of PRE-positive cells in the immune-suppressed group (4193 +/- 2461, 1184 +/- 1502, and 541 +/- 324 at 4, 8, and 12 weeks, respectively) was greater than in immune-competent control animals (292 +/- 506, 193 +/- 173, and 111 +/- 96), but the difference was only statistically significant at 4 weeks. The time-dependent decrease in PRE-positive cells was more pronounced in immune-suppressed animals. Image analysis performed on serial fundus photographs and fluorescein angiograms did not detect any difference in the appearance of the grafts in immune-suppressed versus immune-competent animals.

Conclusions: Systemic immune suppression increased the 4-week survival of porcine RPE xenografts in the albino rabbit subretinal space, but there was poor survival in immune-suppressed and -competent animals 12 weeks after surgery. Many pigment-containing cells 4 or more weeks after surgery were PRE negative, indicating that they are of host origin.
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http://dx.doi.org/10.1167/iovs.02-1175DOI Listing
September 2003

Identification of transplanted retinal pigment epithelium with a novel chromosomal marker.

Curr Eye Res 2003 Feb;26(2):125-31

Department of Ophthalmology, Harkness Eye Institute, Columbia University, New York, NY, USA.

Purpose: To demonstrate the ability of a novel chromosomal marker to identify retinal pigment epithelium (RPE) after xenotransplantation, and determine the short-term correlation between pigment and this nuclear marker.

Methods: Primary pigmented RPE harvested from third trimester fetal pigs were transplanted as microaggregates into the subretinal space of 3 albino rabbits. We then used an in situ probe for a repetitive segment of the porcine chromosome to identify the transplanted RPE.

Results: Pigmented cells were visible in the subretinal space 2 weeks after transplantation. Approximately 70% of pigment-containing cells were also labeled with the porcine chromosomal marker. Labeled cells were predominantly flatter in morphology and close to Bruch's membrane whereas unlabeled cells were rounder and further from Bruch's membrane. The outer nuclear layer thickness was normal above the pigmented monolayer but was decreased over areas containing multiple layers of pigmented cells.

Conclusions: Fetal porcine RPE xenografts can be identified with a nuclear marker for a repetitive segment of the porcine chromosome. The presence of pigment within unlabelled cells suggests that pigment is not a robust marker for transplanted RPE.
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http://dx.doi.org/10.1076/ceyr.26.2.125.14509DOI Listing
February 2003

Renin-angiotensin system and atherothrombotic disease: from genes to treatment.

Arch Intern Med 2003 May;163(10):1155-64

Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Health System, 3400 Spruce Street, Philadelphia, PA 19104, USA.

The renin-angiotensin system plays a central role in the pathogenesis of cardiovascular disease. At the molecular and cellular levels, angiotensin II, the main effector peptide of the system, stimulates key components of atherosclerosis. Trials in animals and humans indicate that blocking renin-angiotensin system pathways decreases atherosclerotic plaque progression and ischemic events. This review provides a broad overview of the entire role of the renin-angiotensin system in atherothrombotic disease, ranging from molecular pathways to human genetics to the latest clinical trials.
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http://dx.doi.org/10.1001/archinte.163.10.1155DOI Listing
May 2003

Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation.

J Am Coll Cardiol 2003 Mar;41(5):879-88

Section of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.

Objectives: We report histological analysis of hearts from patients with end-stage heart disease who were transplanted with autologous skeletal myoblasts concurrent with left ventricular assist device (LVAD) implantation.

Background: Autologous skeletal myoblast transplantation is under investigation as a means to repair infarcted myocardium. To date, there is only indirect evidence to suggest survival of skeletal muscle in humans.

Methods: Five patients (all male; median age 60 years) with ischemic cardiomyopathy, refractory heart failure, and listed for heart transplantation underwent muscle biopsy from the quadriceps muscle. The muscle specimen was shipped to a cell isolation facility where myoblasts were isolated and grown. Patients received a transplant of 300 million cells concomitant with LVAD implantation. Four patients underwent LVAD explant after 68, 91, 141, and 191 days of LVAD support (three transplant, one LVAD death), respectively. One patient remains alive on LVAD support awaiting heart transplantation.

Results: Skeletal muscle cell survival and differentiation into mature myofibers were directly demonstrated in scarred myocardium from three of the four explanted hearts using an antibody against skeletal muscle-specific myosin heavy chain. An increase in small vessel formation was observed in one of three patients at the site of surviving myotubes, but not in adjacent tissue devoid of engrafted cells.

Conclusions: These findings represent demonstration of autologous myoblast cell survival in human heart. The implanted skeletal myoblasts formed viable grafts in heavily scarred human myocardial tissue. These results establish the feasibility of myoblast transplants for myocardial repair in humans.
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http://dx.doi.org/10.1016/s0735-1097(03)00081-0DOI Listing
March 2003

Comparison of fresh and cryopreserved porcine ventral mesencephalon cells transplanted in A rat model of Parkinson's disease.

J Neurosci Res 2002 Aug;69(3):382-96

Department of Cell Transplantation, Diacrin Inc., Charlestown, Massachusetts, USA.

To evaluate whether cryopreservation of porcine ventral mesencephalon cells influences graft survival and function in vivo, we have transplanted either freshly prepared or cryopreserved cells into the striatum of 6-hydroxydopamine-lesioned rats. A single cell suspension of porcine ventral mesencephalon cells from the same isolation either was stored at 4 degrees C and transplanted the next day or was cryopreserved for 4 weeks in liquid nitrogen vapor. The cryopreserved cells were then rapidly thawed, rinsed, and transplanted in the same manner as the fresh cells, with the same dose of viable cells. All animals received daily injections of cyclosporin A to prevent xenograft rejection. To monitor graft function, amphetamine-induced rotation was measured every 3 weeks between 6 and 15 weeks posttransplantation. After sacrifice at 15 weeks posttransplantation, histological methods were used to compare fresh cell and cryopreserved cell transplants with respect to graft survival, differentiation and integration, and host immune response. Cryopreserved cells were found to be either equivalent or in some cases superior to fresh cells with respect to rotational correction, graft survival, graft volume, numbers of graft-derived dopaminergic neurons, and host immune responses. In conclusion, the results indicate that it is feasible to cryopreserve porcine ventral mesencephalon cells for long-term storage of cells prior to transplantation in an animal model of Parkinson's disease.
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http://dx.doi.org/10.1002/jnr.10297DOI Listing
August 2002